CA2093793C - Alkylidene analogs of 1'-aminospiro¬isoquinoline-4(1h),-3'-pyrrolidine|1,2',3,5'(2h)-tetrones useful as aldose reductase inhibitors - Google Patents

Alkylidene analogs of 1'-aminospiro¬isoquinoline-4(1h),-3'-pyrrolidine|1,2',3,5'(2h)-tetrones useful as aldose reductase inhibitors Download PDF

Info

Publication number: CA2093793C
Authority: CA; Canada
Prior art keywords: carbon atoms; aryl; lower alkyl; compound; isoquinoline
Prior art date: 1990-10-12
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Expired - Fee Related

Application number

CA002093793A

Other languages

English (en)

French (fr)

Other versions

CA2093793A1 (en

Inventor

Michael S. Malamas

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Wyeth LLC

Original Assignee

American Home Products Corp

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1990-10-12

Filing date

1991-10-10

Publication date

2001-08-21

1991-10-10 Application filed by American Home Products Corp filed Critical American Home Products Corp

1992-04-13 Publication of CA2093793A1 publication Critical patent/CA2093793A1/en

2001-08-21 Application granted granted Critical

2001-08-21 Publication of CA2093793C publication Critical patent/CA2093793C/en

2011-10-10 Anticipated expiration legal-status Critical

Status Expired - Fee Related legal-status Critical Current

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RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 title claims abstract description 29
125000001118 alkylidene group Chemical group 0.000 title abstract description 10
239000003288 aldose reductase inhibitor Substances 0.000 title description 2
229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims abstract description 58
238000000034 method Methods 0.000 claims abstract description 20
238000002360 preparation method Methods 0.000 claims abstract description 10
-1 4-bromo-2-fluorophenyl Chemical group 0.000 claims description 35
125000000217 alkyl group Chemical group 0.000 claims description 30
125000004432 carbon atom Chemical group C* 0.000 claims description 28
125000003118 aryl group Chemical group 0.000 claims description 24
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
125000003003 spiro group Chemical group 0.000 claims description 13
OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 10
229910052739 hydrogen Inorganic materials 0.000 claims description 10
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
239000001257 hydrogen Substances 0.000 claims description 9
238000006243 chemical reaction Methods 0.000 claims description 8
125000002723 alicyclic group Chemical group 0.000 claims description 5
229910052736 halogen Inorganic materials 0.000 claims description 5
150000002367 halogens Chemical class 0.000 claims description 5
150000002431 hydrogen Chemical class 0.000 claims description 5
239000003937 drug carrier Substances 0.000 claims description 4
229910052760 oxygen Inorganic materials 0.000 claims description 4
229910052717 sulfur Inorganic materials 0.000 claims description 4
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 3
239000008194 pharmaceutical composition Substances 0.000 claims description 3
125000003545 alkoxy group Chemical group 0.000 claims description 2
150000001728 carbonyl compounds Chemical class 0.000 claims description 2
125000000623 heterocyclic group Chemical group 0.000 claims description 2
150000003949 imides Chemical class 0.000 claims description 2
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
125000003107 substituted aryl group Chemical group 0.000 claims description 2
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
238000004519 manufacturing process Methods 0.000 claims 2
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
206010012601 diabetes mellitus Diseases 0.000 abstract description 12
230000008569 process Effects 0.000 abstract description 5
230000009286 beneficial effect Effects 0.000 abstract description 3
239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
230000002265 prevention Effects 0.000 abstract description 2
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 43
238000005160 1H NMR spectroscopy Methods 0.000 description 25
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 16
239000000203 mixture Substances 0.000 description 13
NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 12
WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 9
239000008103 glucose Substances 0.000 description 9
239000007787 solid Substances 0.000 description 9
235000019439 ethyl acetate Nutrition 0.000 description 8
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
241000700159 Rattus Species 0.000 description 7
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
102000004877 Insulin Human genes 0.000 description 6
108090001061 Insulin Proteins 0.000 description 6
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
229940125396 insulin Drugs 0.000 description 6
239000000243 solution Substances 0.000 description 6
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
230000002411 adverse Effects 0.000 description 5
210000000695 crystalline len Anatomy 0.000 description 5
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238000001704 evaporation Methods 0.000 description 5
230000008020 evaporation Effects 0.000 description 5
229930182830 galactose Natural products 0.000 description 5
229910052943 magnesium sulfate Inorganic materials 0.000 description 5
239000003538 oral antidiabetic agent Substances 0.000 description 5
229940127209 oral hypoglycaemic agent Drugs 0.000 description 5
239000002904 solvent Substances 0.000 description 5
GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 4
102000016912 Aldehyde Reductase Human genes 0.000 description 4
108010053754 Aldehyde reductase Proteins 0.000 description 4
239000004480 active ingredient Substances 0.000 description 4
238000001816 cooling Methods 0.000 description 4
BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 4
238000002474 experimental method Methods 0.000 description 4
238000003818 flash chromatography Methods 0.000 description 4
FBPFZTCFMRRESA-GUCUJZIJSA-N galactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-GUCUJZIJSA-N 0.000 description 4
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
239000000725 suspension Substances 0.000 description 4
MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 3
XRXMNWGCKISMOH-UHFFFAOYSA-N 2-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Br XRXMNWGCKISMOH-UHFFFAOYSA-N 0.000 description 3
FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
241000124008 Mammalia Species 0.000 description 3
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
208000017442 Retinal disease Diseases 0.000 description 3
206010038923 Retinopathy Diseases 0.000 description 3
239000002253 acid Substances 0.000 description 3
239000002775 capsule Substances 0.000 description 3
238000002425 crystallisation Methods 0.000 description 3
230000008025 crystallization Effects 0.000 description 3
239000000284 extract Substances 0.000 description 3
201000001421 hyperglycemia Diseases 0.000 description 3
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
230000037361 pathway Effects 0.000 description 3
229920005862 polyol Polymers 0.000 description 3
150000003077 polyols Chemical class 0.000 description 3
210000003497 sciatic nerve Anatomy 0.000 description 3
239000000600 sorbitol Substances 0.000 description 3
239000003039 volatile agent Substances 0.000 description 3
JQPCNISBBBPSOS-UHFFFAOYSA-N 2-(1,3-dimethoxy-1,3-dioxopropan-2-yl)benzoic acid Chemical compound COC(=O)C(C(=O)OC)C1=CC=CC=C1C(O)=O JQPCNISBBBPSOS-UHFFFAOYSA-N 0.000 description 2
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
HPDLIOXFWIOACY-UHFFFAOYSA-N 2-[2-[(4-bromo-2-fluorophenyl)methyl]-4-methoxycarbonyl-1,3-dioxoisoquinolin-4-yl]acetic acid Chemical compound O=C1C2=CC=CC=C2C(C(=O)OC)(CC(O)=O)C(=O)N1CC1=CC=C(Br)C=C1F HPDLIOXFWIOACY-UHFFFAOYSA-N 0.000 description 2
IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 description 2
YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
241000283690 Bos taurus Species 0.000 description 2
206010007749 Cataract diabetic Diseases 0.000 description 2
229910021589 Copper(I) bromide Inorganic materials 0.000 description 2
208000002249 Diabetes Complications Diseases 0.000 description 2
206010012655 Diabetic complications Diseases 0.000 description 2
102000004190 Enzymes Human genes 0.000 description 2
108090000790 Enzymes Proteins 0.000 description 2
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
238000005481 NMR spectroscopy Methods 0.000 description 2
229910006124 SOCl2 Inorganic materials 0.000 description 2
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
238000009825 accumulation Methods 0.000 description 2
239000008280 blood Substances 0.000 description 2
210000004369 blood Anatomy 0.000 description 2
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229910052799 carbon Inorganic materials 0.000 description 2
239000003153 chemical reaction reagent Substances 0.000 description 2
230000001684 chronic effect Effects 0.000 description 2
201000007025 diabetic cataract Diseases 0.000 description 2
210000000188 diaphragm Anatomy 0.000 description 2
239000002552 dosage form Substances 0.000 description 2
150000002148 esters Chemical class 0.000 description 2
238000000338 in vitro Methods 0.000 description 2
238000001727 in vivo Methods 0.000 description 2
AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
208000017169 kidney disease Diseases 0.000 description 2
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
DOSZIOVZSICDQS-UHFFFAOYSA-N methyl 2-[(4-bromo-2-fluorophenyl)methyl]-1,3-dioxo-4h-isoquinoline-4-carboxylate Chemical compound O=C1C2=CC=CC=C2C(C(=O)OC)C(=O)N1CC1=CC=C(Br)C=C1F DOSZIOVZSICDQS-UHFFFAOYSA-N 0.000 description 2
VUNCRCXKVHXKLV-UHFFFAOYSA-N methyl 3-methoxy-1-oxoisochromene-4-carboxylate Chemical compound C1=CC=C2C(C(=O)OC)=C(OC)OC(=O)C2=C1 VUNCRCXKVHXKLV-UHFFFAOYSA-N 0.000 description 2
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230000007823 neuropathy Effects 0.000 description 2
238000010606 normalization Methods 0.000 description 2
239000003921 oil Substances 0.000 description 2
238000007911 parenteral administration Methods 0.000 description 2
FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
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BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
238000000746 purification Methods 0.000 description 2
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BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 2
YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 2
RLTFBWCBGIZCDQ-UHFFFAOYSA-N (4-bromo-2-fluorophenyl)methanamine Chemical compound NCC1=CC=C(Br)C=C1F RLTFBWCBGIZCDQ-UHFFFAOYSA-N 0.000 description 1
ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 1
HQAJGCKMMKDEKH-UHFFFAOYSA-N 2-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-3-fluorobenzoic acid Chemical compound COC(=O)C(C(=O)OC)C1=C(F)C=CC=C1C(O)=O HQAJGCKMMKDEKH-UHFFFAOYSA-N 0.000 description 1
WNOSBCLCJVLFGJ-UHFFFAOYSA-N 2-(6-bromo-4-methoxycarbonyl-2-methyl-1,3-dioxoisoquinolin-4-yl)acetic acid Chemical compound C1=C(Br)C=C2C(C(=O)OC)(CC(O)=O)C(=O)N(C)C(=O)C2=C1 WNOSBCLCJVLFGJ-UHFFFAOYSA-N 0.000 description 1
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FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
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208000033679 diabetic kidney disease Diseases 0.000 description 1
230000003467 diminishing effect Effects 0.000 description 1
230000004064 dysfunction Effects 0.000 description 1
230000000694 effects Effects 0.000 description 1
125000004494 ethyl ester group Chemical group 0.000 description 1
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
229910052731 fluorine Chemical group 0.000 description 1
239000011737 fluorine Chemical group 0.000 description 1
230000004907 flux Effects 0.000 description 1
230000004190 glucose uptake Effects 0.000 description 1
125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
239000003701 inert diluent Substances 0.000 description 1
230000002401 inhibitory effect Effects 0.000 description 1
230000000977 initiatory effect Effects 0.000 description 1
150000007529 inorganic bases Chemical class 0.000 description 1
239000000543 intermediate Substances 0.000 description 1
125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 1
206010023365 keratopathy Diseases 0.000 description 1
210000003734 kidney Anatomy 0.000 description 1
239000008101 lactose Substances 0.000 description 1
ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
239000001095 magnesium carbonate Substances 0.000 description 1
229910000021 magnesium carbonate Inorganic materials 0.000 description 1
235000019359 magnesium stearate Nutrition 0.000 description 1
235000019341 magnesium sulphate Nutrition 0.000 description 1
208000030159 metabolic disease Diseases 0.000 description 1
BRSSFJZXYKOLKP-UHFFFAOYSA-N methyl 2-[(4-bromo-2-fluorophenyl)methyl]-4-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,3-dioxoisoquinoline-4-carboxylate Chemical compound O=C1C2=CC=CC=C2C(C(=O)OC)(CC(=O)OC(C)(C)C)C(=O)N1CC1=CC=C(Br)C=C1F BRSSFJZXYKOLKP-UHFFFAOYSA-N 0.000 description 1
BALMMLYJEIGQJI-UHFFFAOYSA-N methyl 6-bromo-2-methyl-4-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,3-dioxoisoquinoline-4-carboxylate Chemical compound C1=C(Br)C=C2C(C(=O)OC)(CC(=O)OC(C)(C)C)C(=O)N(C)C(=O)C2=C1 BALMMLYJEIGQJI-UHFFFAOYSA-N 0.000 description 1
UGDHGEHKEKBZEO-UHFFFAOYSA-N methyl 6-bromo-3-methoxy-1-oxoisochromene-4-carboxylate Chemical compound C1=C(Br)C=C2C(C(=O)OC)=C(OC)OC(=O)C2=C1 UGDHGEHKEKBZEO-UHFFFAOYSA-N 0.000 description 1
LJXHUQXIFJPEOF-UHFFFAOYSA-N methyl 6-chloro-2-methyl-1,3-dioxo-4h-isoquinoline-4-carboxylate Chemical compound C1=C(Cl)C=C2C(C(=O)OC)C(=O)N(C)C(=O)C2=C1 LJXHUQXIFJPEOF-UHFFFAOYSA-N 0.000 description 1
ITQSBQMGXWWVJN-UHFFFAOYSA-N methyl 6-chloro-2-methyl-4-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,3-dioxoisoquinoline-4-carboxylate Chemical compound C1=C(Cl)C=C2C(C(=O)OC)(CC(=O)OC(C)(C)C)C(=O)N(C)C(=O)C2=C1 ITQSBQMGXWWVJN-UHFFFAOYSA-N 0.000 description 1
ZQKOHJNKCBIYFQ-UHFFFAOYSA-N methyl 6-fluoro-3-methoxy-1-oxoisochromene-4-carboxylate Chemical compound C1=C(F)C=C2C(C(=O)OC)=C(OC)OC(=O)C2=C1 ZQKOHJNKCBIYFQ-UHFFFAOYSA-N 0.000 description 1
239000002480 mineral oil Substances 0.000 description 1
235000010446 mineral oil Nutrition 0.000 description 1
238000002156 mixing Methods 0.000 description 1
230000004048 modification Effects 0.000 description 1
238000012986 modification Methods 0.000 description 1
230000004660 morphological change Effects 0.000 description 1
229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
239000002997 ophthalmic solution Substances 0.000 description 1
150000007524 organic acids Chemical class 0.000 description 1
210000000578 peripheral nerve Anatomy 0.000 description 1
239000008024 pharmaceutical diluent Substances 0.000 description 1
ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 description 1
229960003243 phenformin Drugs 0.000 description 1
239000006187 pill Substances 0.000 description 1
229910000027 potassium carbonate Inorganic materials 0.000 description 1
230000002035 prolonged effect Effects 0.000 description 1
230000000069 prophylactic effect Effects 0.000 description 1
238000010992 reflux Methods 0.000 description 1
210000001525 retina Anatomy 0.000 description 1
238000012453 sprague-dawley rat model Methods 0.000 description 1
239000008107 starch Substances 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
239000008174 sterile solution Substances 0.000 description 1
239000011550 stock solution Substances 0.000 description 1
230000009885 systemic effect Effects 0.000 description 1
239000003826 tablet Substances 0.000 description 1
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
238000012360 testing method Methods 0.000 description 1
238000012956 testing procedure Methods 0.000 description 1
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
229960002277 tolazamide Drugs 0.000 description 1
OUDSBRTVNLOZBN-UHFFFAOYSA-N tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 description 1
229960005371 tolbutamide Drugs 0.000 description 1
238000011200 topical administration Methods 0.000 description 1
208000019553 vascular disease Diseases 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/12—Ophthalmic agents for cataracts
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
General Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Bioinformatics & Cheminformatics (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
Engineering & Computer Science (AREA)
Ophthalmology & Optometry (AREA)
Hematology (AREA)
Urology & Nephrology (AREA)
Diabetes (AREA)
Obesity (AREA)
Neurosurgery (AREA)
Neurology (AREA)
Biomedical Technology (AREA)
Endocrinology (AREA)
Reproductive Health (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Pyrrole Compounds (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Preparation Of Compounds By Using Micro-Organisms (AREA)

CA002093793A 1990-10-12 1991-10-10 Alkylidene analogs of 1'-aminospiro¬isoquinoline-4(1h),-3'-pyrrolidine|1,2',3,5'(2h)-tetrones useful as aldose reductase inhibitors Expired - Fee Related CA2093793C (en)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
US596,889		1990-10-11
US07/596,889 US5068332A (en)	1990-10-12	1990-10-12	Alkylidene analogs of 1'-aminospiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrones useful as aldose reductase inhibitors
PCT/US1991/007467 WO1992006974A1 (en)	1990-10-11	1991-10-10	Alkylidene analogs of 1'-aminospiro[isoquinoline-4(1h),3'-pyrrolidine]-1,2',3,5'(2h)-tetrones useful as aldose reductase inhibitors

Publications (2)

Publication Number	Publication Date
CA2093793A1 CA2093793A1 (en)	1992-04-13
CA2093793C true CA2093793C (en)	2001-08-21

Family

ID=24389149

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA002093793A Expired - Fee Related CA2093793C (en)	1990-10-12	1991-10-10	Alkylidene analogs of 1'-aminospiro¬isoquinoline-4(1h),-3'-pyrrolidine\|1,2',3,5'(2h)-tetrones useful as aldose reductase inhibitors

Country Status (15)

Country	Link
US (1)	US5068332A (de)
EP (1)	EP0555327B1 (de)
JP (1)	JP3115597B2 (de)
KR (1)	KR100212110B1 (de)
AT (1)	ATE175673T1 (de)
AU (1)	AU645866B2 (de)
CA (1)	CA2093793C (de)
DE (1)	DE69130771T2 (de)
DK (1)	DK0555327T3 (de)
ES (1)	ES2126577T3 (de)
GR (1)	GR3029883T3 (de)
LV (1)	LV12444B (de)
PT (1)	PT99185B (de)
SG (1)	SG47811A1 (de)
WO (1)	WO1992006974A1 (de)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US5102886A (en) *	1990-10-12	1992-04-07	American Home Products Corporation	1'-aminospiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrones and analogs thereof useful as aldose reductase inhibitors
DK0618917T3 (da) *	1991-11-25	1997-10-13	American Home Prod	1Amino-2- (benzothiazolyl)methyl spiro isoquinolin-4(1h),3-pyrrolidin -1,2,3,5(2h)-tetroner og analoger deraf, der kan anvendes som aldosereduktaseinhibitorer.
US5189167A (en) *	1991-11-25	1993-02-23	American Home Products Corporation	Alkylidene analogs of 1'-amino-2-[(benzothiazolyl)-methyl]spiro [isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrones useful as aldose reductase inhibitors
HU225920B1 (en) *	1994-01-19	2008-01-28	Sankyo Co	Pyrrolo[2,3-d]pyridazine derivatives, process for their preparation and pharmaceutical compositions containing them
CA2685202C (en) *	2007-03-23	2017-11-28	The Board Of Regents Of The University Of Texas System	Methods for treating allergic asthma
JP4708469B2 (ja)	2008-02-29	2011-06-22	Ｔｄｋ株式会社	バルントランス
KR20220144510A (ko) *	2021-04-20	2022-10-27	에스케이이노베이션 주식회사	신규한 디아자스피로 화합물 및 이의 용도

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US4200642A (en) *	1978-08-21	1980-04-29	Pfizer Inc.	Spiro-oxazolidindiones
IE52879B1 (en) *	1981-05-12	1988-03-30	Ici Plc	Pharmaceutical spiro-hydantoin derivatives
US4575507A (en) *	1985-05-29	1986-03-11	Pfizer Inc.	Spiro-imidazolidines as aldose reductase inhibitors and their pharmaceutical use
AU617541B2 (en) *	1988-10-20	1991-11-28	Wyeth	Spiro-isoquinoline-pyrrolidine tetrones and analogs thereof useful as aldose reductase inhibitors
US4927831A (en) *	1988-10-20	1990-05-22	American Home Products	Spiro-isoquinoline-pyrrolidine tetrones and analogs thereof useful as aldose reductase inhibitors
US5045544A (en) *	1990-05-21	1991-09-03	American Home Products Corporation	N'-alkyl-spiro-isoquinoline-pyrrolidine tetrones and analogs thereof useful as aldose reductase inhibitors

1990
- 1990-10-12 US US07/596,889 patent/US5068332A/en not_active Expired - Lifetime
1991
- 1991-10-09 PT PT99185A patent/PT99185B/pt not_active IP Right Cessation
- 1991-10-10 ES ES91919785T patent/ES2126577T3/es not_active Expired - Lifetime
- 1991-10-10 KR KR1019930701087A patent/KR100212110B1/ko not_active Expired - Fee Related
- 1991-10-10 DE DE69130771T patent/DE69130771T2/de not_active Expired - Fee Related
- 1991-10-10 CA CA002093793A patent/CA2093793C/en not_active Expired - Fee Related
- 1991-10-10 JP JP03518067A patent/JP3115597B2/ja not_active Expired - Fee Related
- 1991-10-10 AT AT91919785T patent/ATE175673T1/de not_active IP Right Cessation
- 1991-10-10 AU AU89228/91A patent/AU645866B2/en not_active Ceased
- 1991-10-10 DK DK91919785T patent/DK0555327T3/da active
- 1991-10-10 WO PCT/US1991/007467 patent/WO1992006974A1/en not_active Ceased
- 1991-10-10 SG SG1996004512A patent/SG47811A1/en unknown
- 1991-10-10 EP EP91919785A patent/EP0555327B1/de not_active Expired - Lifetime
1999
- 1999-04-05 GR GR990400972T patent/GR3029883T3/el unknown
2000
- 2000-01-11 LV LVP-00-04A patent/LV12444B/en unknown

Also Published As

Publication number	Publication date
KR930702347A (ko)	1993-09-08
LV12444B (en)	2000-06-20
LV12444A (en)	2000-03-20
PT99185A (pt)	1992-09-30
PT99185B (pt)	1999-04-30
JPH06502169A (ja)	1994-03-10
KR100212110B1 (ko)	1999-08-02
US5068332A (en)	1991-11-26
AU8922891A (en)	1992-05-20
EP0555327B1 (de)	1999-01-13
DK0555327T3 (da)	1999-08-30
EP0555327A1 (de)	1993-08-18
AU645866B2 (en)	1994-01-27
SG47811A1 (en)	1998-04-17
ES2126577T3 (es)	1999-04-01
ATE175673T1 (de)	1999-01-15
CA2093793A1 (en)	1992-04-13
HK1011356A1 (en)	1999-07-09
WO1992006974A1 (en)	1992-04-30
JP3115597B2 (ja)	2000-12-11
DE69130771D1 (de)	1999-02-25
GR3029883T3 (en)	1999-07-30
DE69130771T2 (de)	1999-05-27

Legal Events

Date	Code	Title	Description
1998-07-17	EEER	Examination request
2005-10-11	MKLA	Lapsed

Publication	Publication Date	Title
US4927831A (en)	1990-05-22	Spiro-isoquinoline-pyrrolidine tetrones and analogs thereof useful as aldose reductase inhibitors
CA2042113C (en)	2001-08-28	Spiro-isoquinoline-pyrrolidines and analogs thereof useful as aldose reductase inhibitors
EP0365324B1 (de)	1994-05-04	Spiro-isochinolin-pyrrolidin-tetrone und Analoge davon, verwendbar als Aldosereduktase-Inhibitoren
HK1004067B (en)	1998-11-13	Spiro-isoquinoline-pyrrolidines and analogs thereof useful as aldose reductase inhibitors
EP0555327B1 (de)	1999-01-13	Alkylidenanaloge von 1'-aminospiro-[isochinolin-4(1h), 3'-pyrrolidin]-1,2',3,5'(2h)-tetronen, verwendbar als aldose reduktase-inhibitoren in vivo
US5045544A (en)	1991-09-03	N'-alkyl-spiro-isoquinoline-pyrrolidine tetrones and analogs thereof useful as aldose reductase inhibitors
US5130425A (en)	1992-07-14	Spiro-lactams and analogs thereof useful as aldose reductase inhibitors
EP0553263B1 (de)	1998-08-05	1'-aminospiro-[isochinolin-4(1h),3'-pyrrolidin]- 1,2',3,5'-(2h)-tetrone und analoge verbindungen als inhibitoren der aldose reduktase in vivo
US5081241A (en)	1992-01-14	Spiro-pyridazines and analogs thereof useful as aldose reductase inhibitors
US5189168A (en)	1993-02-23	1'-amino-2[(benzothiazolyl)methyl]spiro-[isoquinoline-4(1H),3'-pyrrolidine]-1,2'3,5'(2H)-tetrones and analogs thereof useful as aldose reductase inhibitors
EP0618917B1 (de)	1997-03-26	1'-amino-2[(benzothiazolyl)methyl] spiro [isochinolin-4(1h), 3'-pyrrolidine]-1,2',3,5'-tetrone und analoge davon verwendbar als aldosereduktase luhibitoren
US5093496A (en)	1992-03-03	Spiro-isoquinoline-pyrrolidines and analogs thereof useful as aldose reductase inhibitors
US5189167A (en)	1993-02-23	Alkylidene analogs of 1'-amino-2-[(benzothiazolyl)-methyl]spiro [isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrones useful as aldose reductase inhibitors
HK1011356B (en)	2000-05-12	Alkylidene analogs of 1'-aminospiro[isoquinoline-4(1h), 3'-pyrrolidine]-1,2',3,5'(2h)-tetrones useful as aldose reductase inhibitors in vivo
US4983613A (en)	1991-01-08	Isoquinoline acetic acids and acetyl carbamates useful as aldose reductase inhibitors
HK1009601B (en)	2000-05-12	1'-aminospiro[isoquinoline-4(1h),3'-pyrrolidine]-1,2',3,5'(2h)-tetrones and analogs thereof useful as aldose reductase inhibitors in vivo
HK1010368A (en)	1999-06-17	N-alkyl-spiro-isoquinoline-pyrrolidine tetrones and analogs thereof useful as aldose reductase inhibitors
NZ240202A (en)	1994-01-26	1'-aminospiro[isoquinoline-4(1h),3'-pyrrolidine]-1,2',3,5'(2h)-tetrones
CA2324636A1 (en)	1991-11-22	1, 2, 3, 4 - tetrahydro - 1, 3 - dioxo - 4 - isoquinolinecarboxylic acid methyl esters